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Patented Apr. 14, 1959 It has now been found that compounds of thegeneral 2,882,271 formula:

PHARMACOLOGICALLY ACTIVE PIPERAZINE R1 DERIVATIVES AND PROCESSES FORPRE- PARING THEM 5 Y-N NXCH=OH R,

Paul Adriaan J. Janssen, Vosselaar, near Turnhout, Belgium, assignor toLaboratoria Pharmaceutica Dr. C. Janssen N.V., Turnhout, Belgium, alimited-liability company of Belgium in which: Y represents a hydrogenatom or an aralkyl group, X represents a --CH or a CO- group, and NoDrawing Application April 3, 1957 R R and R represent a hydrogen or ahalogen atom Serial No. 651,179 or an alkoxy or alkyl group, containingnot more than five carbon atoms, are active antihistaminics with a lowClaims priority, application Netherlands April 20, 1956 sedative actionif X represents a group, and

7 i ((1, 2 0 240 strong sedatives with only a slight antihistaminicactivity,

if X represents a CO group. This invention relates to newpharmacologically active So e of the antihistaminics possess a verystrong piperazine derivatives and processes for preparing them.activity, comparable with the activity of l-p-chlorobenzo- It is knownthat several asymmetrically substituted hydryl-4-m-methyl-benzylpiperazine and/or have a very piperazine derivatives possess anantihistaminic action. g lasting action- The sedative lie-tones Possessa tran- Some substituted benzohydryl-benzyl-piperazines show aquilliling action 011 test animals, but give no rise to very strong andlong lasting antihi-staminic action, and hyp not even in the highestdosesy at ve moreover in addition have a rather important sedative sideaction there is to be understood in the present specification efiect.Consequently these compounds are also used as inhibition of thespontaneous motility of test animals. sedatives. In their action theseketones can best be compared with It is a principal object of thisinvention to provide reserpine, the Well known tranquillizing Rauwolfia,alkacompounds which possess antihistaminic and sedative acloid. (Thisclass of compounds is also known as trantion and which are low intoxicity. Another object of quillizing agents.) The grade of thesedative action this invention is to separate the antihistaminic actionfrom cannot be shown in numbers. the sedative side-efiect. This sedativeside-eifect can be All of these compounds are very low in toxicity. Auseful in itself. Investigations were therefore made for notable actioncan be obtained by administering only antihistaminics having a minorsedative eifect, as well as small fractions of the lethal dose (LD thesefracfor sedatives having a minor antihistaminic action. It tions beingof the order of magnitude of 4 In the was found that strengthening orweakening of the sedafollowing table several of the compounds obtainedactive effect in relation to the antihistaminic action could 35 cordingto the present invention are described with refbe promoted with acertain group of piperazine derivatives erence to the foregoing formula,together with their physiin a simple manner. cal and pharmacologicaldata.

Table Y-N N'-XCH=CH R: Melting Activity No. Salt point,

degrees Rs Y X R1 Ra Ra Ant.h. Sed.

OH: H H H Base 20 (B.P. 191 at 18.5 mm. Hg) CO H H H Base 68 CH2 Ht-oiHn H do 119 0 00 H t-(nH, H do 128-129 00 H P0411 H H01.-- 250-25500 H H H Base 168 OH, H H H H01.-- 192 C O H 01 H Base- 140. 5 0H, H 01H HC1 -162 CO H t04Ht H Base 183-185 0H2 H t-G4Hs H .d0 130.5-133 CO HOCH; H HC1 1 221 OH, H OCHa H Base.- 126-132 (OaHs)2CH- CO OCH: OCH:OCH: do- 178'179.6

p-Cl-CaH; OH: H H H H01.-. 200-201 CuHs- H 16 -oi-oflni 00 H CH: HH01.-- 150-153 CaHs H.-

17 pC1CsH OH; H CH: H H01.-. 177-178 R i l l CaHs- H- 18 pC1OsH4 CO OH:H H H01.-. -173 CaH5- H- 19 p-ClC5H4 OH: CH: H H HC1 1176200 CaHsCH- Seefootnote at end of table.

TableContinued 1E1 Y-N N -XC H=CH-Q R; Melting Activity No. Salt point,

Ra degrees Y X R; Ra R; Ant. h. Sed.

p-ClCaHt CO H iCaH1 H Base 149.5

C6H50H 21 p-Cl-C.,H Q 0 H iCaH1 H H01... 153

CaHs- H 22 pOl-UeH4 CH2 H i.OaH1 H HC1 164 CsHs- H pClOaH4 CO H t-QHg HBase -170.5-171 CuHs- H- 24. pOlCaH OH; H tG4H H H01-.- 167-175 OaHs-GH-25 P-CICBH4 CO H 00H; H Base- 131-133 CaHs H- 26 p-C1C6H( OH: H 00113 HHO1 179-180 CaHs- H 27 p-OHs-CuHr CO H tC4H H Base 144-145 CsHs- H- 28pCHsCaH4 OH: H t-GrHg H H01--- 188-2101 CeHs-CH 29 p1-CaH1CaH4 CO Ht-(hHq H BaSe 169-172 O0H5CH- 30 p--i-CaH1CeH4 OH: H t-ChHn H HUI-..195-198 C6H6-CH 3l pCHaO-CHr CO H t-O4H H Base 139-142 CuHr-CH 32 pCHaOOH4 OH: H t-C4H9 H HG1 163165 CaHs-CH- 33 p-OHaO-CalL 00 H (2-O4H9 HBase. 139

pCl-CoHr-CH 34 p-CH30C5H& CH: H t-CgHg H HCl 157-158 p-ClOaH4GH- 85pCH::-C5H CO H t-O H H Base 100-102 pGlCaHr-CH 36 p-GH3CH4 OH: H 15-011; H H01--. 205-206 p-Cl-CH;OH

37 -iO3H?0@H CO H tC H H Base 158-160 1)CiCuH4-CH 38 pi-CaHr-CH; OH; Ht-G4Hn H HCl 201-205 p-CiCoH4CH- Dec.

The compounds according to the invention can be and R having the meaningas hereinbefore defined, while prepared by reaction of piperazine withhalides Hal represents a halogen atom.

In the examples hereinafter given, only the second Bl phase of theprocess is indicated, since the first phase proceeds in an analogousrnanner. It is, however, preferred are: as:aaasizaasfgzuar the R3Further the compounds in which X represents a CO- and HalY in anydesired sequence, in the presence of a hydrogen halide binding agent,the symbols Y, X, R R

group, can be converted in a. simple manner into the correspondingcompounds, in which X represents a CH; group, Without attacking thedouble bond, by reduction with lithium aluminium hydride.

e1 6 Gr? The invention is further explained by reference to the Example3 followmg examples: A solution of 0.07 mole of4-chlorobenzohydrylchloride Example 1 and 0.14 mole of l-cinnamylpiperazine in 500 cc. of

. toluene are boiled for 2 days, if desired in the presence grams.(01165 mole) of 4'(temary butyl) 5 of 0.15 mole of potassium carbonate.The toluene is namoyl chloride in 400 cc. of dry benzene are mixed evaorated and the residue extracted with ether, this W1 th 93 grams ofpfperazme m solii tion is filtered and the ether evaporated. The resi-600 of dry berizene t boiled for 30 under due obtained is extracted withacetone, which solution reflux. The reaction mixture 18 left overnightat about is saturated with hydrochloric acid gas The hydm ig i g zf gi33 3 fi gmgfi f s gfig l0 chloride of 1-cinnamyl-4-(4-chlorobenzohydryl)piperawith 50-200 cc. of a dilute aqueous hydrochloric acid Zmepreclpltates 1s filtered and punfied by recrystalhza' tion solution. Theunreacted 1-(4-chlorobenzohydryl) piperazine can be recovered from theaqueous layer obtained giizfi the base can be punfied dlrecfly byfracnonal gfi 1t alkalme' In this manner all compounds according to theinvene chloroform layer is washed with a dilute aqueous tion can beprepared and also those in which X=CO sodium hydroxide solution,thereafter with water, and is yields amount to f 6O 85 ercent finallydried over potassium carbonate. The residue, p

What I claim is which is obtained after evaporation of the chloroform,1s dissolved by heating in a mixture of 25 percent of toluene A compoundof the structural formula and 75 percent of heptane. On cooling thissolution to about 20 C. the 1-(4-tertiary butyl cinnamoyl)-4-(4-chlorobenzohydryl) piperazine precipitates. Yields are O NXCH=CHobtained of from 66 to 81 grams (70-86 percent). The CHPCH,

melting point is 170.5171 C., the ultraviolet spectrum in isopropanolshows a maximum at 287.5 m n with an extinction of about 27,900. Thecalculated molecular weight is 473.04 (C H N OCI), whereas 478.6 and477.2 was found. The chlorine content amounts to 9.50 perwherein Ar andAr are members of the class consisting of phenyl, methoxyphenyl, (loweralkyl)-phenyl and chlorophenyl groups, wherein X is a member of theclass consisting of the methylene and carbonyl groups and cent(theoretically also Percent)- wherein Z is a member of the classconsisting of phenyl, Example 2 chlorophenyl, (lower alkyl)-phenyl,methoxyphenyl and trimethoxyphenyl groups. To 0.04 mole of 1-(4-methylcinnamoyl)-4-(4-chloro- 2. A compound of the structural formulabenzohydryl) piperazine in 50 cc. of ether 0.03 mole of 3.1-(4-tertiary-butyl cinnamoyl)-4-(4-chlorobenzohylithium aluminiumhydride in 250 cc. of ether are slowly dryl) piperazine. added. Therebysufiicient heat is produced to cause the 4. Acompound of the structuralformula o1 oHr-orn (lower alkyl) (ll-G CHr-CH: (lower alkyl) CH N N ee0e=ee@ Q CHs-C 2 ether to boil. After 30 minutes the mixture is heated5. 1-(4-methoxy cinnamyl)-4-benzohydryl piperazine. so that boilingunder reflux may continue for a few 6. 1-cinnamyl-4-benzohydrylpiperazine. hours, after which the excess of lithium aluminium hy- 7.1-(4-methy1 cinnamyl)-4-(4-chlorobenzohydryl) pidride is decomposed withwater in which, preferably, perazine. some sodiumpotassiumtartrate isdissolved. After separation of the basic material with ether, thehydrochloride References Cited in the file of fins Patent is formed inthe Well known way with hydrochloric acid UNI STATES PATENTS gas, whichhydrochloride is further purified by crystallization. The 1-(4-methylcinnamyl)-4-(4-chlorobenzo- 2,777,849 Bach et a1 "Ian-15,1957 hydryl)piperazine hydrochloride is thus obtained. OTHER REFERENCES All otherreductions with lithium aluminium hydride Gaylord, N. G.: Reduction WithComplex Metal Hyare performed in an analogous manner. The yields 0drides, pages 124, 645; Interscience, New York (1956). amount to from50-90 percent. Papa et al.: J. Am. Chem. Soc., 72 (3885-6) (1950).

1. A COMPOUND OF THE STRUCTURAL FORMULA